Hypertensive patients (HTs) have impaired nitric oxide (NO) activity, but the mechanism underlying this abnormality is unknown. We have recently observed an increased endothelin (ET) vasoconstrictor tone in HTs related to increased production of the peptide. In the present study, we investigated whether the increased ET activity of HTs could contribute to their impaired NO-dependent vasodilator function. To this end, the vasodilator responses to acetylcholine (ACh; 7.5, 15, and 30 ug/min), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP; 0.8,1.6, and 3.2 ug/min), an exogenous NO donor, were assessed before and after nonselective blockade of ETA and ETB receptors by combined infusion of BQ-123 (ETA blocker; 100 nmol/min) and BQ-788 (ETB blocker; 50 nmol/min for 60 min) in 6 HTs. Drugs were infused into the brachial artery and forearm blood flow (FBF) was measured by strain-gauge plethysmography. The increases in FBF from baseline induced by the 3 doses of ACh were significantly potentiated by nonselective blockade of ET receptors (0.47+/-0.21(mean+/-SEM), 2.73+/-2.08, and 4.71+/-2.48 mL/min/dL before vs 3.38+/-1.41, 6.06+/-2.56, and 8.67+/-3.06 mL/min/dL after ET antagonism; P=0.01). In contrast, ET receptor blockade did not significantly modify vascular responsiveness to the 3 doses of SNP (2.85+/-0.95, 4.76+/-1.47, and 7.18+/-2.27 mL/min/dL before vs 3.28+/-1.01, 4.94+/-1.48, and 6.5+/-1.84 mL/min/dL after ET antagonism (P=0.97). These findings indicate that endothelial vasodilator function in HTs improves after blockade of ET receptors, suggesting that an increased ET activity may be involved in the pathophysiology of their endothelial dysfunction.